Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

In vitro bioaccessibility and bioavailability of iron from breads fortified with microencapsulated iron

Iron deficiency is the most prevalent mineral deficiency in the world. Food fortification offers an alternative to standard oral iron therapy, which often causes unpleasant side effects. In this study, bread was fortified with either ferrous sulphate or ferrous fumarate. To prevent undesired organoleptic changes in colour, odour and taste, iron compounds were introduced in the form of microcapsules. Eight types of bread were prepared using conventional fermentation or sourdough and fortified with one of four types of microcapsule. The in vitro bioaccessibility and bioavailability of the iron were determined using the human epithelial adenocarcinoma cell line Caco-2, preceded by digestion in a dynamic gastrointestinal digester, which mimics the upper gastrointestinal tract of an adult human. The bioaccessibility of the iron after digestion of the fortified breads varied from 41.45 to 99.31%. The iron transport efficiency varied widely, from 1.16 to 13.78%. Generally, both bioaccessibility and transport efficiency were higher in the samples of breads prepared by conventional fermentation. The mRNA expression of DMT1 and IREG1, cellular iron transporters which serve as molecular markers of iron movement across the intestinal border, was not statistically significant

The SWI/SNF KlSnf2 Subunit Controls the Glucose Signaling Pathway To Coordinate Glycolysis and Glucose Transport in Kluyveromyces lactis

In Kluyveromyces lactis, the expression of the major glucose permease gene RAG1 is controlled by extracellular glucose through a signaling cascade similar to the Saccharomyces cerevisiae Snf3/Rgt2/Rgt1 pathway. We have identified a key component of the K. lactis glucose signaling pathway by characterizing a new mutation, rag20-1, which impairs the regulation of RAG1 and hexokinase RAG5 genes by glucose. Functional complementation of the rag20-1 mutation identified the KlSNF2 gene, which encodes a protein 59% identical to S. cerevisiae Snf2, the major subunit of the SWI/SNF chromatin remodeling complex. Reverse transcription-quantitative PCR and chromatin immunoprecipitation analyses confirmed that the KlSnf2 protein binds to RAG1 and RAG5 promoters and promotes the recruitment of the basic helix-loop-helix Sck1 activator. Besides this transcriptional effect, KlSnf2 is also implicated in the glucose signaling pathway by controlling Sms1 and KlRgt1 posttranscriptional modifications. When KlSnf2 is absent, Sms1 is not degraded in the presence of glucose, leading to constitutive RAG1 gene repression by KlRgt1. Our work points out the crucial role played by KlSnf2 in the regulation of glucose transport and metabolism in K. lactis, notably, by suggesting a link between chromatin remodeling and the glucose signaling pathway

Measurement of the Fluctuations in the Number of Muons in Extensive Air Showers with the Pierre Auger Observatory

The successful installation, commissioning, and operation of the Pierre Auger Observatory would not have been possible without the strong commitment and effort from the technical and administrative staff in Malargue. We are very grateful to the following agencies and organizations for financial support: Argentina-Comision Nacional de Energia Atomica, Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Gobierno de la Provincia de Mendoza, Municipalidad de Malargue, NDM Holdings and Valle Las Lenas; in gratitude for their continuing cooperation over land access; Australia-the Australian Research Council; BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundacao de Amparo a Pesquisa do Estado de Rio de Janeiro (FAPERJ), Sao Paulo Research Foundation (FAPESP) Grants No. 2019/10151-2, No. 2010/07359-6, and No. 1999/05404-3, Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC); Ministry of Education, Youth and Sports of the Czech RepublicGrants No. MSMT CR LTT18004, No. LM2015038, No. LM2018102, No. CZ.02.1.01/0.0/0.0/16_013/0001402, No. CZ.02.1.01/0.0/0.0/18_046/0016010, and No. CZ.02.1.01/0.0/0.0/17_049/0008422; France-Centre de Calcul IN2P3/CNRS, Centre National de la Recherche Scientifique (CNRS), Conseil Regional Ile-de-France, Departement Physique Nucl ' eaire et Corpusculaire (PNC-IN2P3/CNRS), Departement Sciences de l'Univers (SDU-INSU/CNRS), Institut Lagrange de Paris (ILP) Grant No. LABEX ANR-10-LABX-63 within the Investissements d'Avenir Programme Grant No. ANR11-IDEX-0004-02; Germany-Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Finanzministerium Baden-Wurttemberg, Helmholtz Alliance for Astroparticle Physics (HAP), Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF), Ministerium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, Ministerium fur Wissenschaft, Forschung und Kunst des Landes Baden-Wurttemberg; Italy-Istituto Nazionale di Fisica Nucleare (INFN), Istituto Nazionale di Astrofisica (INAF), Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), CETEMPS Center of Excellence, Ministero degli Affari Esteri (MAE); Mexico-Consejo Nacional de Ciencia y Tecnologia (CONACYT) Grant No. 167733, Universidad Nacional Autonoma de Mexico (UNAM), PAPIIT DGAPA-UNAM; The Netherlands-Ministry of Education, Culture and Science, Netherlands Organisation for Scientific Research (NWO), Dutch national e-infrastructure with the support of SURF Cooperative; Poland-Ministry of Science and Higher Education, Grant No. DIR/WK/2018/11, National Science Centre, Grants No. 2013/08/M/ST9/00322, No. 2016/23/B/ST9/01635, and No. HARMONIA 5-2013/10/M/ST9/00062, UMO-2016/22/M/ST9/00198; Portugal -Portuguese national funds and FEDER funds within Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia (COMPETE); Romania-Romanian Ministry of Education and Research, the Program Nucleu within MCI (PN19150201/16N/2019 and PN19060102), and project PN-III-P1-1.2-PCCDI-2017-0839/19PCCDI/2018 within PNCDI III; Slovenia-Slovenian Research Agency, Grants No. P1-0031, No. P1-0385, No. I00033, No. N1-0111; Spain-Ministerio de Economia, Industria y Competitividad (FPA2017-85114-P and FPA2017-85197-P), Xunta de Galicia (ED431C 2017/07), Junta de Andalucia (SOMM17/6104/UGR), Feder Funds, RENATA Red Nacional Tematica de Astroparticulas (FPA2015-68783-REDT), and Maria de Maeztu Unit of Excellence (MDM-2016-0692); U.S.Department of Energy, Awards No. DE-AC0207CH11359, No. DE-FR02-04ER41300, No. DE-FG0299ER41107, and No. DE-SC0011689, National Science Foundation, Grant No. 0450696, The Grainger Foundation, Marie Curie-IRSES/EPLANET, European Particle Physics Latin American Network, and UNESCO.We present the first measurement of the fluctuations in the number of muons in extensive air showers produced by ultrahigh energy cosmic rays. We find that the measured fluctuations are in good agreement with predictions from air shower simulations. This observation provides new insights into the origin of the previously reported deficit of muons in air shower simulations and constrains models of hadronic interactions at ultrahigh energies. Our measurement is compatible with the muon deficit originating from small deviations in the predictions from hadronic interaction models of particle production that accumulate as the showers develop.Argentina-Comision Nacional de Energia AtomicaANPCyTConsejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)Gobierno de la Provincia de MendozaMunicipalidad de MalargueNDM HoldingsValle Las LenasAustralian Research CouncilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)Fundacao de Apoio a Pesquisa do Distrito Federal (FAPDF)Financiadora de Inovacao e Pesquisa (Finep)Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio De Janeiro (FAPERJ)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) 2019/10151-2 2010/07359-6 1999/05404-3Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC)Ministry of Education, Youth & Sports - Czech Republic MSMT CR LTT18004 LM2015038 LM2018102 CZ.02.1.01/0.0/0.0/16_013/0001402 CZ.02.1.01/0.0/0.0/18_046/0016010 CZ.02.1.01/0.0/0.0/17_049/0008422France-Centre de Calcul IN2P3/CNRSCentre National de la Recherche Scientifique (CNRS)Region Ile-de-FranceCentre National de la Recherche Scientifique (CNRS)Departement Sciences de l'Univers (SDU-INSU/CNRS)French National Research Agency (ANR) LABEX ANR-10-LABX-63 ANR11-IDEX-0004-02Federal Ministry of Education & Research (BMBF)German Research Foundation (DFG)Finanzministerium Baden-WurttembergHelmholtz Alliance for Astroparticle Physics (HAP)Helmholtz AssociationMinisterium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-WestfalenMinisterium fur Wissenschaft, Forschung und Kunst des Landes Baden-WurttembergItaly-Istituto Nazionale di Fisica Nucleare (INFN)Istituto Nazionale Astrofisica (INAF)Ministry of Education, Universities and Research (MIUR)CETEMPS Center of ExcellenceMinistry of Foreign Affairs and International Cooperation (Italy)Consejo Nacional de Ciencia y Tecnologia (CONACyT) 167733Universidad Nacional Autonoma de Mexico (UNAM), PAPIIT DGAPA-UNAMNetherlands-Ministry of Education, Culture and ScienceNetherlands Organization for Scientific Research (NWO)Dutch national e-infrastructureSURF CooperativePoland-Ministry of Science and Higher Education DIR/WK/2018/11National Science Centre, Poland 2013/08/M/ST9/00322 2016/23/B/ST9/01635 HARMONIA 5-2013/10/M/ST9/00062 UMO-2016/22/M/ST9/00198Portugal -Portuguese national fundsFEDER funds within Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia (COMPETE)Romania-Romanian Ministry of Education and Research, the Program Nucleu within MCI PN19150201/16N/2019 PN19060102Romania-Romanian Ministry of Educatio n and Research, the Program Nucleu within PNCDI III PN-III-P1-1.2-PCCDI-2017-0839/19PCCDI/2018Slovenian Research Agency - Slovenia P1-0031 P1-0385 I00033 N1-0111Spain-Ministerio de Economia, Industria y Competitividad FPA2017-85114-P FPA2017-85197-PXunta de Galicia European Commission ED431C 2017/07Junta de Andalucia SOMM17/6104/UGREuropean CommissionRENATA Red Nacional Tematica de Astroparticulas FPA2015-68783-REDTMaria de Maeztu Unit of Excellence MDM-2016-0692United States Department of Energy (DOE) DE-AC0207CH11359 DE-FR02-04ER41300 DE-FG0299ER41107 DE-SC0011689National Science Foundation (NSF) 0450696Grainger FoundationMarie Curie-IRSES/EPLANETEuropean Particle Physics Latin American NetworkUNESC

Mth1 regulates the interaction between the Rgt1 repressor and the Ssn6-Tup1 corepressor complex by modulating PKA-dependent phosphorylation of Rgt1

Glucose uptake, the first, rate-limiting step of its utilization, is facilitated by glucose transporters. Expression of several glucose transporter (HXT) genes in yeast is repressed by the Rgt1 repressor, which recruits the glucose-responsive transcription factor Mth1 and the general corepressor complex Ssn6-Tup1 in the absence of glucose; however, it is derepressed when Mth1 is inactivated by glucose. Here we show that Ssn6-Tup1 interferes with the DNA-binding ability of Rgt1 in the absence of Mth1 and that the Rgt1 function abrogated by Ssn6 overexpression is restored by co-overexpression of Mth1. Thus Mth1 likely regulates Rgt1 function not by modulating its DNA-binding activity directly but by functionally antagonizing Ssn6-Tup1. Mth1 does so by acting as a scaffold-like protein to recruit Ssn6-Tup1 to Rgt1. Supporting evidence shows that Mth1 blocks the protein kinase A–dependent phosphorylation of Rgt1 that impairs the ability of Rgt1 to interact with Ssn6-Tup1. Of note, Rgt1 can bind DNA in the absence of Ssn6-Tup1 but does not inhibit transcription, suggesting that dissociation of Rgt1 from Ssn6-Tup1, but not from DNA, is necessary and sufficient for the expression of its target genes. Taken together, these findings show that Mth1 is a transcriptional corepressor that facilitates the recruitment of Ssn6-Tup1 by Rgt1